The physiological role of the renin-angiotensin system is to regulate blood pressure and to maintain sodium and volume homeostasis. The key events in this system are the conversion of the polypeptide angiotensinogen to the decapeptide angiotensin I (AI) and the subsequent cleavage of the latter to give the octapeptide angiotensin II (AII). The latter peptide is a potent vasoconstrictor and a potentiator of aldosterone release. Due to potent pressor effects, AII plays a significant role in hypertension and as such has been the target for the development of antihypertensive agents.
One approach to finding such agents is to search for potent inhibitors of the angiotensin converting enzyme. Inter alia, the latter enzyme catalyzes the conversion of AI to AII. This approach has met with success and a number of such agents are used therapeutically to treat hypertension. Another approach is to find specific inhibitors of renin, an aspartyl protease which cleaves angiotensinogen to AI. Since angiotensinogen is the only known natural substrate for renin, this approach has the desirable feature of being aimed at a potential antihypertensive agent with a single mode of action.
In the pursuit of this goal, a great deal of attention has been given to designing renin inhibitors which mimic the natural substrate angiotensinogen. Much of this effort has been focused on the design of analogous substrates incorporating therein a non-cleavable mimic (i.e. a transition state analog) of the renin cleavage site (i.e. Leu-Val) of human angiotensinogen. As a result, a number of potent renin inhibitors have been identified in the laboratory, and the ability of renin inhibitors to lower blood pressure and to reduce plasma renin activity has now been demonstrated in the clinic. For a recent review on renin inhibitors, see W. J. Greenlee, Medical Research Reviews, 10, 173 (1990). Nevertheless, progress toward obtaining the ideal renin inhibitor continues to be plagued with problems of low oral absorption, limited bioavailability and rapid elimination, mainly due to the peptidic nature of the inhibitors presently under investigation. Hence, there is a need for a readily administered, effective renin inhibitor.
The renin inhibitors of the present application belong to the class of transition state analog inhibitors of renin. They are characterized by having a N-(amidomethyl)succinamoyl moiety incorporated into their structure. This feature, in combination with their non-peptidic character and their relatively lower molecular weight, apparently contribute beneficially to the stability, absorption and bioavailability of the inhibitors. Another feature of the present inhibitors is their relative specificity for renin as compared to other aspartyl proteases.
The following references exemplify past efforts that have been made in the search for renin inhibitors with improved characteristics:
W. J. Greenlee et al., European patent application 278 158, published Aug. 17, 1988; PA0 A. A. Patchett et al., U.S. Pat. No. 4,839,357, issued Jun. 13, 1989; PA0 D. J. Kempf et al., European patent application 402 646, published Dec. 19, 1990; PA0 P. D. Williams et al., U.S. Pat. No. 5,001,113, issued Mar. 19, 1991; PA0 H. Heitsch et al., Canadian patent application 2,025,093, published Mar. 13, 1991; PA0 W. J. Greenlee et al., U.S. Pat. No. 5,006,511, issued Apr. 9, 1991; PA0 P. D. Williams, Canadian patent application 5 2,034,524, published Jul. 20,1991; PA0 H. N. Weller and D. E. Ryono, U.S. Pat. No. 5,055,466, issued Oct. 8, 1991; and PA0 S. H. Rosenberg et al., U.S. Pat. No. 5,063,208, issued Nov. 5, 1991.